Aire Mutations and Autoimmune Diseases

Abstract

The autoimmune regulator (AIRE) gene is crucial for the development of normal central immunological tolerance and prevention of autoimmunity. In this chapter, we will see how mutations in AIRE cause a rare autosomal recessive disease, autoimmune polyendocrine syndrome type 1 (APS-1). APS-1 patients display a variety of endocrine and ectodermal manifestations where the majority of patients develop at least two of the three main components of adrenocortical insufficiency (Addison’s disease), hypoparathyroidism and chronic mucocutaneous candidiasis. Further, we will look into how the disease-causing mutations found in AIRE have been important in revealing the functional properties of the AIRE protein and its domains. Interestingly, a subset of specific, heterozygous AIRE mutations directly causes common organ-specific autoimmunity with propensity for pernicious anemia and vitiligo. Multiple single cases and families with heterozygous mutations in the first plant homeodomain (PHD1) zinc finger presented with dominant inheritance, later presentation, milder phenotypes, and reduced penetrance compared to the classical APS-1 caused by recessive mutations in the gene. We will also discuss how AIRE has been implicated in other, more common autoimmune diseases and look into the reported dosage response of AIRE. Hopefully, the emerging ease and lower cost of exome- and genome sequencing will aid in revealing the full involvement of AIRE in more common autoimmune diseases. As we will see, the evidence so far suggests that AIRE’s role in common autoimmune disorders is still to be fully determined.